The use of thromboxane A.sub.2 receptor antagonists for arterial thrombosis is well recognized, but their application in venous thrombosis and as adjuncts to heparin is not established. The anticoagulant heparin, which is the choice drug for preventing venous clots, is much less effective in the arterial circulation. Likewise, aspirin and other antiplatelet drugs impede arterial thrombosis, but are generally ineffective against venous thrombosis. This dichotomy exists because of important differences in the mechanisms of clot formation in the venous and arterial arms of the vascular tree. Arterial clots (white thrombus) consist primarily of platelets, which have aggregated in response to vessel injury. Venous clots (red thrombus) differ in that stasis of blood flow and activation of coagulation (plasma thickening) combine with vessel damage to generate a red blood cell rich mass. This is not to say that coagulation is not involved in arterial thrombosis, or that platelets do not have a role in venous clot formation, only that the magnitude of impact differs in each particular instance.
There is indeed room for improvement over the use of heparin for prophylaxis of DVT, especially after total hip replacement (Hampson et al., "Failure of low-dose heparin to prevent deep-vein thrombosis after hip-replacement arthroplasty." Lancet 2:795-797, 1985). Recent therapeutic approaches have focused on combination therapies involving agents selective for the individual components responsible for venous clot formation, which include vessel injury, blood coagulation and blood stasis. It has been suggested that inhibition of two of these three components would maximize the potential for preventing DVT (Comerota et al, "Combined dihydroergotamine and heparin prophylaxis of postoperative deep vein thrombosis; proposed mechanism of action." Am. J. Surgery 150:39-44, 1985). Dihydroergotamine is a vasoactive drug used to increase venous tone and thereby reducing blood stasis in vessels where pooling of blood is a potential thrombotic hazard. Dihydroergotamine has been found to act synergistically with heparin in reducing the incidence of post-surgical DVT (Kakkar et al., "Prophylaxis for postoperative deep-vein thrombosis." JAMA 241:39-42, 1979). A combination of dihydroergotamine and heparin with lidocaine has been marketed by Sandoz (Embolex) for prophylaxis against DVT and pulmonary embolism associated with major abdominal, thoracic or pelvic surgery.
The combination of aspirin with heparin was investigated in venous thrombosis during the 1970's. Some of the results were promising (Vinazzer et al., "Prophylaxis of postoperative thromboembolism by low dose heparin and by acetylsalicyclic acid given simultaneously. A double blind study." Throm. Res. 17:177-184, 1980), although bleeding complications which were associated with the addition of aspirin made this combination unfavorable (Yett et al., "The hazards of aspirin plus heparin." New Eng. J. Med. 298:1092, 1978). The inability to reverse the action of aspirin was no doubt a disadvantage in these studies. In contrast, the activity of the thromboxane A.sub.2 receptor antagonist SQ 30,741 would reverse rapidly upon cessation of intravenous administration. There are also theoretical reasons why aspirin might have lesser efficacy when compared to SQ 30,741. Treatment of human platelets with another cyclooxygenase inhibitor was found to cause expression of procoagulant activity (Barrowcliffe et al., "Procoagulant activity of arachidonic acid metabolites." Br. J. Pharmacol. 92:129-132, 1987). This appeared to result from a deleterious diversion of platelet arachidonic acid metabolism into other pathways. Such a reaction or inhibition of beneficial prostaglandins, including prostacyclin, would not be expected with a thromboxane A.sub.2 receptor antagonist.
Aspirin may also be effective against pulmonary embolism associated with major surgery (Jennings, J. J., et al., J. Bone Joint Surgery, 58A:926-928, 1976).
It has been found that although thromboxane A.sub.2 receptor antagonists (SQ 30,741 and BM 13,505) are capable of reducing venous thrombosis by approximately 50% in rats, this is less than the effect achieved with heparin and required fairly high doses of the TxA.sub.2 antagonists. For these reasons TxA.sub.2 -receptor antagonists alone might not prove to be therapeutically beneficial against DVT.